Polycystic kidney disease (PKD) is a genetic disorder characterized by the growth of numerous cysts in the kidneys of a subject. PKD is among the most common life-threatening genetic diseases in the world and is a leading cause of end-stage renal failure and a common indication for dialysis or renal transplantation (Wilson, N. Engl. J. Med. 2004, 350, 151-164). The kidneys filter wastes and extra fluid from the blood to form urine and also regulate amounts of certain vital substances in the subject. When cysts form in the kidneys, they are filled with fluid. PKD cysts can profoundly enlarge the kidneys while replacing much of the normal structure, resulting in reduced kidney function and leading to kidney failure. PKS includes autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD). ADPKD is the more common inherited form of PKD, whereas ARPKD is a rare inherited form. It has been reported that mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively, may be responsible for ADPKD (Gallagher et al., Adv. Chronic Kidney Dis. 2010, 17(2): 118-130; The European Polycystic Kidney Disease Consortium, Cell 1994, 78:725; The International Polycystic Kidney Disease Consortium, Cell 1995, 81:289-298; Mochizuki et al., Science 1996, 272:1339-1342; The European Polycystic Kidney Disease Consortium, Cell 1994, 77, 881-894). A causative gene ARPKD has been thought to be PKHD1, which encodes fibrocystin/polyductin (FPC).
PKD can also cause cysts in the liver and problems in other organs, such as blood vessels in the brain and heart. For example, polycystic liver disease (PLD) is an inherited condition characterized by the presence of multiple scattered cysts of biliary origin throughout the liver parenchyma (Fedeles et al., Nature Genetics 2011, 43(7):639-648; Qian et al., Hepatology 2003, 37, 164-171). PLD occurs frequently as an extra-renal manifestation of ADPKD, but it also exists as a distinct dominantly inherited genetic entity without kidney cysts (autosomal dominant PLD (ADPLD)). Mutations in PRKCSH or SEC63 may underlie isolated ADPLD (Reynolds et al., Am. J. Hum. Genet. 2000, 67, 1598-1604; Li et al., Am. J. Hum. Genet. 2003, 72, 691-703; Davila et al., Nat. Genet. 2004, 36, 575-577; Drenth et al., Nat. Genet. 2003, 33, 345-347).
PC1, PC2, and FPC, along with one Meckel syndrome gene product (MKS3) (Smith et al., Nat. Genet. 2006, 38, 191-196), have been reported to be the only integral membrane proteins mutated in cilia-associated fibrocystic diseases (Sharma et al., Curr. Top. Dev. Biol. 2008, 85, 371-427). ADPKD and ADPLD are also unique in that they may be the only dominantly inherited traits among the cilia-associated diseases (Menezes et al., Methods Cell Biol. 2009, 94, 273-297).
Subjects with PKD (e.g., ADPKD) may be treated by hemodialysis, peritoneal dialysis, or renal transplantation. Treatment of PLD (e.g., ADPLD) may include cyst aspiration, cyst fenestration, liver resection, and liver transplantation. Currently, there are no FDA-approved therapeutic drugs that directly target PKD. Several clinical trials are underway testing the cAMP inhibitor (Tolvaptan) or excessive intake of water as means to slow down the progression of PKD. Certain mTOR inhibitors, such as rapamycin, have been studied in clinical trials, but those mTOR inhibitors have not shown significant clinical effectiveness. Therefore, there remains a need for improved treatment of PKD and PLD.